Prodrugs are derivatized forms of drugs that following administration are converted or metabolized to an active form of the drug in vivo. Prodrugs are used to modify one or more aspects of the pharmacokinetics of a drug in a manner that enhances the therapeutic efficacy of a drug. For example, prodrugs are often used to enhance the oral bioavailability of a drug. To be therapeutically effective, drugs exhibiting poor oral bioavailability may require frequent dosing, large administered doses, or may need to be administered by other than oral routes, such as intravenously. In particular, many drugs with sulfonic acid groups exhibit poor oral bioavailability.
Intramolecular cyclization prodrug strategies have been used to modify the pharmacokinetics of drugs (Bundgaard in “A Textbook of Drug Design and Development,” Krogsgaard-Larsen and Bundgaard Eds., Harwood Academic, Philadelphia, 1991, pp. 113-192; Bungaard and Nielsen, U.S. Pat. No. 5,073,641; Santos et al., Bioorganic & Medicinal Chemistry Letters, 2005, 15, 1595-1598; Papot et al., Curr Med Chem—Anti-Cancer Agents, 2002, 2, 155-185; and Shan et al., J Pharm Sciences 1997, 86(7), 765-767). Intramolecular cyclization release prodrug strategies have been applied to drugs containing sulfonic acid functional groups. Prodrugs comprising a substituted neopentyl sulfonate ester derivative in which the neopentyl group is removed in vivo by unmasking a nucleophilic heteroatom bonded to a substituted neopentyl moiety followed by intramolecular cyclization to generate the parent drug in the sulfonic acid or sulfonic acid salt form have been described (Roberts and Patch, U.S. Pat. No. 5,596,095; and Roberts et al., Tetrahedron Lett 1997, 38(3), 355-358). In such prodrugs the nucleophilic heteroatom can be nitrogen or oxygen and the nitrogen or oxygen nucleophile can be masked with any amine or alcohol protecting group, respectively, capable of being deprotected in vivo. Roberts and Patch also disclose that the masked nucleophilic group can be a carboxylic ester, e.g., —OCOR where R can be aryl, substituted aryl, heteroaryl, C1-8 alkyl, arylalkyl, or heteroarylalkyl. However, Roberts and Patch do not provide biological or pharmacological data to indicate which if any of the substituted neopentyl sulfonate esters release the prodrug in vivo and would therefore be useful for enhancing the oral bioavailability of the corresponding drug.
3-(Acetylamino)propylsulfonic acid (also referred to as N-acetylhomotaurine), acamprosate,
is a derivative of homotaurine, a naturally occurring structural analog of γ-aminobutyric acid (GABA) that appears to affect multiple receptors in the central nervous system (CNS). As an antiglutamatergic agent, acamprosate is believed to exert a neuropharmacological effect as an antagonist of N-methyl-D-aspartate (NMDA) receptors. The mechanism of action is believed to include blocking of the Ca2+ channel to slow Ca2+ influx and reduce the expression of c-fos, leading to changes in messenger RNA transcription and the concomitant modification to the subunit composition of NMDA receptors in selected brain regions (Zornoza et al., CNS Drug Reviews, 2003, 9(4), 359-374; and Rammes et al., Neuropharmacology 2001, 40, 749-760). In addition, acamprosate may block GABAB receptors (Daost, et al., Pharmacol Biochem Behav. 1992, 41, 669-74; and Johnson et al., Psychopharmacology 2000, 149, 327-344). Similar mechanisms are believed to be associated with the activity of other glutamate modulators such as riluzole, N-acetylcysteine, β-lactams, amantadine, lamictal, memantine, neramexane, remacemide, ifenprodil, and dextromethorphan.
Other diseases or disorders known to be associated with modulation of NMDA activity and for which modulators of NMDA receptor activity are clinically useful include psychotic disorders such as schizophrenia and schizoaffective disorder; mood disorders such as anxiety disorders including posttraumatic stress disorder and obsessive-compulsive disorder, depression, mania, bipolar disorder; and somatoform disorders such as somatization disorder, conversion disorder, hypochondriasis, and body dysmorphic disorder; movement disorders such as Tourette's syndrome, focal dystonia, Huntington's disease, Parkinson's disease, Syndeham's chorea, systemic lupus erythematosus, drug-induced movement disorders, tardive dyskinesia, blepharospasm, tic disorder, and spasticity; substance abuse disorders such as alcohol abuse disorders, narcotic abuse disorders, and nicotine abuse disorders; cortical spreading depression related disorders such as migraine, cerebral damage, epilepsy, and cardiovascular; sleeping disorders such as sleep apnea; multiple sclerosis; and neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Recently, acamprosate has been found to be effective in treating tinnitus, or noise originating in the ear, a common disorder (de Azevedo et al., 109th Meeting and OTO EXPO of the Am. Acad. Otolaryngology—Head and Neck Foundation, Los Angeles, Calif., Sep. 25-28, 2005; Azevedo et al, Rev. Bras. Otorrinolaringol. Engl. Ed., 2005, 71, 618-623; and Azevedo et al., WO 2007/082561 A2). Acamprosate analogs (Berthelon et al., U.S. Pat. No. 6,265,437) and salt forms of acamprosate analogs (Durlach, U.S. Pat. No. 4,355,043) are also reported to have therapeutic potential.
There is also evidence that acamprosate may interact with excitatory glutamatergic neurotransmission in general and as an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5) in particular (De Witte et al., CNS Drugs 2005, 19(6), 517-37). The glutamatergic mechanism of action of acamprosate may explain the effects of acamprosate on alcohol dependence and suggests other activities such as in neuroprotection. Dysregulation of the mGluR5 receptor has been implicated in a number of diseases and mGluR5 antagonists have been shown to be effective in treating depression, pain, anxiety disorders, alcohol abuse disorders, drug abuse disorders, nicotine abuse disorders, neurodegenerative disorders such as Parkinson's disease, diabetes, schizophrenia, and gastrointestinal reflux disease.
Acamprosate is a polar molecule that lacks the requisite physicochemical characteristics for effective passive permeability across cellular membranes. Intestinal absorption of acamprosate is mainly by passive diffusion and to a lesser extent by an active transport mechanism such as via an amino acid transporter (Más-Serrano et al., Alcohol 2000, 4(3); and 324-330; Saivin et al., Clin Pharmacokinet 1998, 35, 331-345). As a consequence, the oral bioavailability of acamprosate in humans is only about 11%. The mean elimination half-life of acamprosate following intravenous infusion (15 min) is 3.2±0.2 h. Efforts to enhance the gastrointestinal absorption and oral bioavailability of acamprosate include co-administrating the drug with polyglycolysed glycerides (Saslawski et al., U.S. Pat. No. 6,514,524). Acamprosate prodrugs exhibiting enhanced absorption from the lower gastrointestinal tract have the potential to increase the oral bioavailability of the drug and to facilitate administration of acamprosate using sustained release oral dosage forms.